The goal of this project is to determine role of C-type natriuretic peptide (CNP) signaling, a recently identified endochondral growth pathway, during childhood inflammatory disease. Chronic inflammatory diseases of childhood such as juvenile rheumatoid arthritis (JRA), Crohn's disease cause arrest or delay in linear growth of affected children. This growth retardation is most noticeable in children affected with JRA, with sometimes unacceptable growth discrepancies that require surgical correction. In addition to the longitudinal growth delay that occurs with inflammation, there is decreased bone density and trabeculation in adjacent bone that predisposes to fracture. Interactions between chronic inflammation and known systemic and local growth factors fail to fully explain the mechanisms of inflammation related growth delay. Current treatments such as growth hormone therapy are not sufficient to overcome the growth disturbance in children with active disease. This project will determine how the CNP endochondral signaling pathway is affected by and can itself alter the consequences of inflammation in bones and joints. In mice, loss of function mutations in the CNP gene or in its receptor NPR2 causes dwarfism. We have recently found in humans that the autosomal recessive skeletal disorder Acromesomelic Dysplasia Maroteaux type (AMDM) is caused by loss of function mutations in the CNP receptor, natriuretic peptide 2 (NPR2). CNP and the down stream effector molecules of its signaling pathway has been shown to interact with molecules that play important roles in inflammation and cartilage degradation in the joints and growth plates such as vascular endothelial growth factor, mitogen activated protein kinases and matrix metalloproteinases. I hypothesize that CNP endochondral signaling pathway is affected by and can alter the consequences of inflammation in bones and joints. I propose to determine the activity of the CNP signaling system during experimental murine arthritis in vivo and ex vivo using transgenic mice that over express the CNP that we have recently made. My specific aims are: 1) to determine the effects of active inflammation on CNP regulated endochondral growth and joint cartilage hemostasis in a murine model of inflammatory arthritis in-vivo and ex-vivo. 2) to determine the interactions between molecules that are increased due to proinflammatory cytokine stimuli such as MAPKs, MMPs and VEGF and CNP signaling pathway in the growth plate and joint cartilage using in-vitro and ex-vivo chondrocyte tissue cultures experiments.